Researchers Unveil New Techniques For Editing Genes

Researcher David Liu's lab at the Broad Institute developed a method of fixing single-letter misspellings in DNA.Casey Atkins

This story was written byMatthew Herperand Ellie Kincaid.

Researchers have invented two new techniques that expand the ability of human beings to edit the genetic code of living things, potentially paving the way for new medical and agricultural applications.

The techniques both build on the discovery of CRISPR, a bacterial immune system that biologists have hacked into a gene-editing tool. One, published in Nature, allows the editing of single-letter DNA misspellings in genes, a major cause of illness, to be accomplished far more easily and efficiently. A second discovery, published in Science, uses a new CRISPR enzyme to edit not only DNA but also RNA, the chemical messenger that living things use to turn DNA code into the proteins that are the building blocks of living bodies. The discoveries were made by different groups at the Eli & Edythe Broad Institute of MIT and Harvard.

Most genetic diseases are caused because of single-letter misspellings in DNA. A quick review. The blueprints of living things are written in DNA in a code of chemical base pairs: guanine (G), cytosine (C), adenine (A), and thymine (T). Because G pairs with C and A pairs with T, a DNA molecule can be split like a zipper, and two copies of it are created. But sometimes, a letter gets switched. In fact, half of harmful human single-letter genetic mutations involve G getting switched with A or T with C.

Researchers in the laboratory of Broad researcher David Liu came up with a solution. They took advantage of the fact that a simple chemical change can turn adenine (A) into a chemical called inosine, which the body treats just like guanine (G). They pressured bacteria to evolve a new enzyme that could change adenine to inosine, and could be paired with the most common CRISPR enzyme, Cas9, to make genetic edits. Using CRISPR involves cutting DNA, and waiting for the cell to fix it. The new technique is simpler and creates fewer edits. “When the goal is simply to fix a point mutation, base editing offers simpler and cleaner solution,” Liu said on a conference call with reporters.

Luhan Yang, the chief scientific officer of biotech startup eGenesis, which is genetically editing pigs to make their organs transplantable in humans, says she tried to develop (and patent) a similar technique almost a decade ago, but couldn't get it to be efficient enough. CRISPR, she says, allowed Liu's group to solve this problem. She says the new technique could be very useful in making genetic edits without causing re-arrangements of the DNA, a problem with current techniques.

The second technique makes it possible to edit a whole other species of genetic chemical: RNA. It's possible that life started as RNA, and some viruses, like HIV, use the chemical as their genetic material. But in most living things, it's a messenger, which ferries the genetic recipes encoded in DNA to organs in cells that use them to cook up proteins.

Feng Zhang of the Broad Institute of MIT participates in a panel discussion at the National Academy of Sciences international summit on the safety and ethics of human gene editing, Tuesday, Dec. 1, 2015, in Washington. (AP Photo/Susan Walsh)

Researchers working in the lab of Feng Zhang were looking for a way to use CRISPR in cells in the brain, which don't divide and therefore can't be edited just by making cuts and waiting for the cell to fix the damage during replication. Why not look at RNA? Working with Eugene Koonin at the National Institutes of Health, they found a CRISPR enzyme called Cas13. "It’s normally a protein that recognizes RNA and destroys RNA by cutting RNA," says Zhang. (Bacteria use CRISPR enzymes to cut and destroy viruses.)

The paper shows that editing of the RNA with CRISPR is possible. But outside researchers said they were not sure if the technique would prove useful.

"The DNA editing paper is indeed interesting because it expands the kinds of targeted changes that can be made in DNA without introducing breaks," said Jennifer Doudna, a UC Berkeley professor who is widely credited with co-discovering CRISPR. (She and Zhang are generally seen as competitors.) "Challenges to practical use in the clinic or in agriculture include delivery (the editing enzyme is very large) and precision, since edits occur at sites neighboring the desired position. As for the RNA editing paper, I can't think of an application given the modest/incomplete levels of editing and the limited type of editing reported. It would be preferable to simply edit the DNA."

George Church, a Harvard researcher who has also been involved with CRISPR nearly since the beginning, echoed Doudna's concerns. One advantage of editing DNA is that it can be brief and permanent -- do it once, and you're done. There are a lot of RNA products to edit in a cell, he argues. He called the Liu paper "especially interesting" because it could be used against such a wide variety of mutations, but notes that the most common mutations that cause diseases like cystic fibrosis, Huntington's, and Fragile X syndrome are still not amenable to CRISPR, and says his lab is searching for new enzymes that could change that.*

Zhang counters that the RNA approach could result in drugs that are given once every few weeks, and that it could be particularly fit for neurons. Yang offers that, regardless, the new technique will be invaluable in understanding how RNA editing happens in living things. There's no word yet on how the two new technologies will be commercialized.

*A previous version misstated the types of genes and enzymes Church was referring to.

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